Oral clefts are classified into two groups of the genetic, embryologic, and epidemiologic grounds: cleft lip with or without cleft palate [CL(P)] and isolated cleft palate (CP). Orientals, especially Japanese, are known to be at a higher risk for CL(P), whereas incidences of CP are less predictable with the exception of individuals of Hawaiian ancestry at higher risk. Our earlier comparative study showed a significant role of major gene in the Danish population, whereas multifactoral inheritance alone can explain the family resemblance in Japanese in Japan. The aims of this study are: (1) to examine how generally racial differences in genetic etiology of CL(P) are extended, (2) to test whether pheontypic differences in CL(P) have genetic basis, (3) to discriminate alternative modes of inheritance of CP, (4) to assess by stimulation the effects of genetic heterogeneity, and errors in ascertainment and incidence estimates on detection of major genes in threshold characters, (5) to examine whether maternal, hybridity, and recombination effects tested on interracial crosses in Hawaii are consistent with the evidence from family studies, and (6) to study further the nature of the sex ratio deviations of CL(P) and CP cases. The aims specified in (1) through (3) are largely achieved by studies of family resemblance through complex segregation analysis under the mixed model. Parameters of interest are displacement, degree of dominance, gene frequency, and transmission probability for major genes, and heritability for multifactorial inheritance. The analysis will be carried out on the existing data, as well as new data on CL(P) and CP collected on U.S. whites. Comparisons will be made between racial groups in Hawaii and groups outside Hawaii. For the stimulation study, families will be generated by the Monte Carlo method in the computer creating genetic heterogeneity. The genetic models will be tested on these families. The effects of interracial crosses will be investigated based on the diallele model using 560,000 live births born in Hawaii during the period of 1942-1983. The sex ratio study will be based on the reproductive history and sex distribution of mothers of the probands. This study is expected to contribute to delineation of genetic etiology of CL(P) and CP, which is essential for correct estimation of recurrence risks for genetic counseling and eventual prevention of these defects.